It is a known fact that nutritional interventions (enteral or parenteral nutritional support) in critical patients enable the reversion of catabolic conditions and anabolism stimulation, leading to improved recovery and survival rate.
A patient in a critical condition is one who, for example, is subjected to chemotherapy, who suffers generalised septicaemia, viral infection, surgery, burns, trauma, cancer, immunosuppressive treatment, malnutrition or generally any who require long periods of hospitalisation. All these clinical situations have a negative effect on the capacity of the immune response, increasing the risk of opportunistic infections, post-surgical complications and certain associated toxicities, for example, those resulting from chemotherapy or radiotherapy, delaying recovery and reducing the chance of survival.
The immune response is not only compromised in critical patients but also in humans and animals under stress, especially at early ages. In these cases the risk of oportunistic infections increases, especially those related to the respiratory and digestive systems. A clear example of the infections related to stress at early ages comes from animal production. In animals reared under commercial conditions these infections are especially relevant. For example, in calves, the first peak of respiratory diseases often emerges at four weeks of age, causing substantial economic losses due to medication and growth depression (H. J. Postema et al., Tijdschr Diergeneeskd. 1, 112(11), 665-671 (1987); H. J. van der Fels-Klerx et al., Preventive Veterinary Medicine 51(1-2), 75-94 (2001); O. Angen et al., Veterinary Microbiology 137(1-2), 28, 165-171 (2009); T. Autio et al., Veterinary Microbiology 119(2-4), 31, 256-265 (2007)).
In addition there is an increasing concern about the overuse of antimicrobials to threat opportunistic infections due to the appearance of antimicrobial resistance (A. G. Mathew et al., Foodborne Pathog. Dis. 4(2), 115-133 (2007)).
Nucleotides are low-weight intercellular compounds that play a role in almost all biochemical processes. They occur naturally in foodstuffs, although in limited quantities (<400 mg/100 g). Tissues with high rates of cellular proliferation, such as those of the immune and gastrointestinal systems, are not able to meet the need for nucleotides by through novo synthesis alone, meaning the preferential route is recovery of nucleotides from diet. In situations where stress affects the immune system (patients in critical situation) dietary supplementation with nucleotide formulations is essential to maintain the humoral and cellular response of the immune system (A. Gil, European Journal of Clinical Nutrition, 56 suppl 3, S1-S4 (2002)). It has been specifically shown that exogenous nucleotide supplements stimulate proliferation of lymphoid cells and the lymphoproliferative response to alloantigens and mitogens. This supplementation also contributes to T-lymphocyte response, increases delayed cutaneous hypersensitivity response, increases graft rejection, reverts immunosuppression associated to malnutrition, increases resistance to certain infections, regulates the number of natural killer (NK) cells and macrophages, and promotes the synthesis of immunoglobulin (J. Maldonado et al, Early Human Development, 65 Suppl., S69-S74 (2001)).
Supplementation with nucleotides has been studied in randomised clinical studies (RCS) conducted in critical patients. A meta-analysis of 13 studies concluded that supplementation has no effect on mortality, but does significantly reduce the incidence of infections and the duration of hospitalisation (R. J. Beale et al., Crit. Care Med., 27, 799-805 (1999)).
On the other hand, some studies have shown that dietary supplementation with certain polysaccharides from extracts of fungi, yeast or bacteria (especially α-glucans and β-glucans) has a positive effect on the immune response.
β-glucans are a heterogeneous group of glucose polymers that have been studied during recent years because of their biological effects on mammals. It has been described that β-glucans act as activators of the immune system and cellular response modifiers. The binding of β-glucans to their specific intestinal receptors leads to modulation in the expression of cytokines, transcription and growth factors that regulate the immune response. This regulation has demonstrated benefits for palliating immunosuppression and for preventing the haematopoiesis associated to chemotherapy and radiotherapy. Additionally, it has been shown that β-glucans confer certain anticarcinogen activity, preventing oncogenesis and metastatis (D. Akramienė et al., Medicina (Kaunas), 43(8), 597-606 (2007)).
α-glucans are a group of glucose polymers, bound by links α(1-4) and/or α(1-6). An example for obtaining these compounds from an extract of Lentinus edodes, a basidiomycete fungus, is described in patent documents EP 733647 (see also U.S. Pat. No. 5,756,318), U.S. Pat. No. 6,831,067 and U.S. Pat. No. 7,169,762. Researches carried out during the last ten years in humans and animals have shown that oral supplementation with these polysaccharides has an immunomodulatory effect. In animal model an increase in TNFα levels has been described, which significantly reduces the size of metastatic tumours in rats. At the same time, they prevent the hepatotoxicity induced by carbon tetrachloride and they protect rats treated with cytosine arabinoside (used in chemotherapy). Studies carried out in humans have demonstrated that oral supplementation with polysaccharides reduces the recurrence of hepatocellular carcinoma and in general, the side effects associated to chemotherapy (E. L. Spierings et al., J Nutr Sci Vitaminol, 53, 536-539 (2007)).
There are documents that describe the use of a combination of nucleotides with other nutrients to palliate immunosuppression in critical patients. For example, in patent application EP 367724 (see also U.S. Pat. No. 5,231,085), a combination of nucleotides with arginine and polyunsaturated fatty acids to improve the immune response in humans has been described.
Although nucleotides and extracts rich in polysaccharides from fungi, yeasts and bacteria administered alone can lead to a certain level of immunostimulation or reduction of immunosuppression associated with the critical condition, to date, it has neither been described nor suggested the combination of a nucleobase or a source of nucleobases (for example, nucleotides, nucleosides, RNA or DNA) with a polysaccharide from an extract of fungi, yeast or bacteria. The effect of this combination on the immune response has neither been described.